Phillips, Nelson F.
Design of supramolecular insulin hexamers as long-acting depot
General Research Subject: Type 2 Diabetes
Project Start Date: July 1, 2013
Project End Date: June 30, 2015
Diabetes Type: Type 2 diabetes
The United States and much of the world is facing a pandemic of diabetes mellitus (DM) due to the increased prevalence of both Type 1 and Type 2 diabetes mellitus. The medical and economic burdens of this pandemic and its grave implications for long-term complications have provided the motivation to improve diabetes treatment technologies. The central objective of insulin replacement therapy in diabetes mellitus (DM) is glycemic control. The importance of tight control has motivated extensive efforts to develop novel insulin analogs with a range of short- and long-acting pharmacokinetic properties. Whereas fast-acting analogs are essential for the management of Type 1 DM, basal insulin analogs enhance glycemic control in multi-injection regimens and are of overarching importance in Type 2 diabetes mellitus.
We seek to develop a second-generation long-acting insulin analog by a a novel bottom-up zinc stapling strategy that creates an assembly of supramolecular insulin hexamers in the subcutaneous depot. A second modification of the insulin molecule further stabilizes the supramolecular insulin complex. This depot formed by a pH-dependent precipitation upon subcutaneous injection act as a stable and ultra-long acting insulin reservoir. To our knowledge, this proposal represents the first structure-based use of ¡°zinc-stapling and electrostatic strategy¡± as a design element in a protein therapeutic. The design and development of ultra-flat basal insulin analog formulations promise to enable patients to mimic with greater precision endogenous mechanisms of hormonal regulation. The long term translational goal is a one-a-week basal insulin for the treatment of type 2 diabetes.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
The central objective of insulin replacement therapy in diabetes mellitus (DM) is glycemic control. Whereas fast-acting analogs are essential for the management of Type 1 diabetes mellitus and key to the operation of insulin pumps, long acting insulin analogs enhance glycemic control in multiinjection regimens and are of prime importance in Type 2 diabetes mellitus. We seek to develop a second-generation long-acting insulin analog with increased potency and stability.
This project will enable us to re-engineer the insulin molecule so as to form an assembly of supramolecular insulin hexamers in the subcutaneous depot creating a prolonged mode of action. The design and development of ultra-flat basal insulin analog formulations promise to enable patients to mimic with greater precision the normal insulin regulation.
If a person with diabetes were to ask you how your project will help them in the future,
how would you respond?
The two current basal analogs (glargine and detemir) have improved profiles but with rising glycaemia during day-time especially in combination therapy. Insulins with a truly stable 24-hour basal blood glucose-lowering effect will require only once a day dosing. In Type 2 patients controllable by either mealtime or basal insulin alone, the basal analogs are preferred because of their reduced risk of weight gain. Given the emerging pandemic of the metabolic syndrome and Type2 diabetes mellitus, there is a global need for such basal analogs. The long term translational goal of our research is a one-a-week basal insulin for the treatment of type 2 diabetes.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
My lifelong awareness of diabetes mellitus stems from a family member who was diagnosed with this disease and her efforts in glycemic control. Circumstances and opportunities had led me to acquire training and knowledge in metabolism, enzymology, and protein chemistry. About 12 years ago I decided to apply these skills into the re-design of Insulin that would generate analogs with optimized pharmacokinetic properties. The current ADA innovation award will enable my team to develop basal Insulin analogs that not only has a protracted mode of action but also has superior potency and stability properties.
The goals of the research exemplify an innovative strategy to modify the pharmacokinetics of a subcutaneous protein depot. To our knowledge, this research approach represents the first structure-based use of Zinc-stapling and electrostatic strategy as a design element in a protein therapeutic. The designed basal insulin is expected to pave the way in the long term translation goal of a once-a-week insulin therapy.
In what direction do you see the future of diabetes research going?
Scientists believe that stem cell research, especially embryonic stem cell research, holds great promise in the search for a cure and better treatments for diabetes. It is envisioned that this research will offer a cure for type 1 diabetes as well as controlling type 2 diabetes. However, until these objectives are achieved, Insulin therapy is the choice. It is remarkable that after decades since its atomic-level structure was solved, insulin continues to inspire molecular innovation motivated by unmet clinical needs. Unmet needs relate directly to risks faced by patients; with short term risks reflecting treatment-related hypoglycemia on the one hand, and hyperglycemic excursions on the other.
The next-generation insulin analogs seek to enhance the safety and convenience by which patients can achieve metabolic control. At the frontier for basal insulin analog design -for self-organization within a subcutaneous depot- will require the integration of structural design and nanotechnology.
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